Derivatives of organic amino alcohols and methods for obtaining the same



Patented July 24, 1951 UNITED STATES PATENT OFFICE DERIVATIVES OF ORGANIC AMINO ALCO- HOLS AND METHODS FOR OBTAINING THE SAME Loren M. Long, Grosse Pointe Woods, Mich., as

signer to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing; Application September 24, 1949,

Serial No. 111,711

8 Claims. (Cl- 260- 490) This application is a continuation-in-part of acyl radi al and R d m have t game mmy -pendins application ri o. ,111 canoe as given above. These transformations March 1 1 w abandoned, and h may be diagrammatically illustrated as follows. vention relates to derivatives of organic amino R1 alcohols and to methods for obtaining the same. l More particularly, the invention relates to D ketonic amino alcohol compounds having the R: 0

general formula,

R1 0 NH-R w B0 eanne A l H R, alkaline condensaand to the production of amino diol products of R, o mi-R" C m 0 NH-R"- MHM re ms, R: e i B:

n 1 B l [H] a, on NH-B." r a, on NE-n" te ee em m go-en-en-cmomi R: R1 formula, 2 It will be readily appreciated by those skilled B1 on NILE in the art that the amino diol compounds of the g CH OR, I invention exist in structural as well as optical v isomeric forms. The term structural isomer R1 or form as used herein refers to the cis or trans,

, therefrom. where is hydrogen or an m m. that is, the planar relationship of the polar groups cal, R1 and R2 are the same or different and repon the two esymmetl'ic carbon. atomsslime resent hydrogen halogen lower alkyl or lower some of the isolation procedures hereinafter dealkoxy radicals and R is hydrogen o an acy] scribed lead to the separation of these diastereo radical. The term acyl as used herein includes isomers, the Products having the 015 Structural lower aliphatic acyl, halogen substituted lower fem Wm hereinafter he referred to as the anphatic acyl, benzbyly substituted bemoyl; ular form to differentiate them from the trans araliphatic acyl and the like acyl radicals. r P- structural fo m. Such cis com- In accordance with the invention an w-acyl- Pounds are Products wherein the two most hi y amino acetophenone derivative is condensed with I pole! of the groups on the two asymmetric formaldehyde in thcplfesence of an alkaline conhen atoms he on the same side)! the Plane of densation catalyst to Obtain a ketomc compound 40 the two carbon atoms. Conversely, the trans or pseudo compounds are those wherein the two of formula r most highly polar groups lie on opposite sides NIL-R l of the plane of the two carbon atoms. In the De-eH-OILOH absence of any such designation of the struce, tural form, the product is the unresolved mixture 1 ms. which is either converted to the corresponding g i mgg ggr i g designated by reduction or acylated to obtain an as A in the above diagram the formaldehyde may acyl derivative of formula" be supplied to the reaction mixture in a number 0 of different forms. For example, formaldehyde g2 e -hn cn,o l gas, aqueous or alcoholic solutionsof formal- R dehyde, paraformaldehyde and other formaldehyde yielding polymers may be used. In most Which is then reduced to the Corresponding amino cases it has been found preferable to use an exmonoacylated 101 c u Where R" is an cess of formaldehyde, usually up to aboutfour or 3 five mols, in order to insure completeness of the condensation reaction.

A variety of solvents, alkaline condensation catalysts and reaction conditions may also be employed. As solvents water and either aqueous or anhydrous lower aliphatic alcohols are particularly advantageous but moist dialkyl ethers and dioxane-water mixtures may also be used. The alkaline condensation catalysts used in this phase of the invention may be organic bases, inorganic bases or inorganic salts of acidic or pseudo acidic organic compounds. Some representative types of these catalysts are the hydroxides, oxides, carbonates, bicarbonates and amides of alkali or alkaline earth metals: alkali metal alkoxides; alkaline earth alkoxides; alkali metal phenolates; alkali metal salts of lower aliphatic carboxylic acids; organic tertiary amines and quaternary ammonium hydroxides of organic tertiary amines. In general, the weakly alkaline catalysts such as sodium bicarbonate, potassium bicarbonate, calcium hydroxide. pyridine. triethvlamine. N-ethyl morpholine, N,N-dimethyl aniline and the like are preferred since they make the reaction much easier to control. When strongly alkaline catalysts such assodium hydroxide. potassium hydroxide, potassium carbonate, sodium methylate, sodium ethylate and the like are used, care must be taken to remove or inactivate the catalyst as soon as the reaction is completed in order to prevent the conversion of the desired product to the corresponding methylene bis compound by a dehydration and coupling reaction. Although the amount of the catalyst is not critical and can vary from a few hundredths or thousandths of a mol to one mol or more, it

is preferable from the standpoint of yields to use only enough to bring about a relatively rapid reaction. In most cases 0.05 mol or less is sumcient.

The temperature used in carrying out this methylolation reaction, as well as the time re- 75 C. in a time varying from a few minutes to several hours. When strongly alkaline catalysts are used the reaction proceeds very rapidly and p is usually complete in a few minutes at room temperature or below. However, when mildly alkaline catalysts are employed the reaction is not so rapid and usually requires from fifteen minutes to several hours at room temperature or slightly above, that is, at about 25 to 50 C.

The reduction of the a-acylamino-fl-hydroxypropiophenone compounds or'of the corresponding fi-acyloxy derivatives to the amino diol products of the invention, shown by B in the above diagram, can be carried out in several different ways. For example, it may be carried out using hydrogen gas in conjunction with a metal hydrogenation catalyst; an oxidizable aluminum alkoxide or nascent hydrogen generated in the reaction mixture by the interaction of a metal are usually sufllcient to bring. about reduction within a reasonable time and hence are preferred. some examples of the hydrogenation catalysts which can be employed are Raney nickel, palladium, palladium oxide, platinum, platinum oxide and the like while suitable solvents for the reduction include lower aliphatic alcohols and aqueous solutions of the same, lower aliphatic acids, dioxane-water mixtures and the like.

When using the nascent hydrogen method of I reduction, metals or alloys such as sodium, po-

tassium, calcium, sodium amalgam, potassium amalgam, iron and the like are caused to react with the solvent used for the reaction to produce hydrogen in the reaction mixture. Some examples of the solvents which can be used are lower'aliphatic alcohols such as methanol, ethanol and isopropanol; lower aliphatic acids such as acetic acid; aqueous mixtures of either lower aliphatic alcohols or acids; moist dialkyl ethers such as moist diethyl ether and lower aliphatic alcohol-acid-water mixtures. Specific combinations of these metals and solvents which have been found to be particularly effective in bringing about the reduction of the ketonlc compounds are sodium, potassium or calcium and absolute ethanol or methanol; sodium or potassium amalgam in moist ether, ethanol or acetic acid; and iron in dilute ethanol containing acetic acid.

When an oxidizable aluminum alkoxide is used as a reductant for the ketonic compounds of the invention the reaction is carried out at a tem-. perature between about 20 and 125 C. in a lower' aliphatic alcohol which is, preferably, the one corresponding to the alkoxide. The use of alkoxides of secondary alcohols such as isopropanol and secondary butyl alcohol is preferred since these alkoxides are more readily oxidized and hence milder reaction conditions can be employed. Regardless of the acylated ketonic compound used as the starting material the product obtained under these reduction conditions consists almost totally of the corresponding l-phenyl-2-acylamido-propane-l,3-diol compound due to the simultaneous hydrolysis of the terminal acyl group which takes place when a fi-acyloxya-acylamidopropiophenone is employed as the with an acid. lower aliphatic alcohol, water or starting material.

Although all of the foregoing methods of reduction can be used with about equal success in most instances there are, of course, instances where the use of one method is preferable. Similarly, the optimal conditions or reagents used in conjunction with one method vary somewhat in the individual cases. For example, where the,

ketonic compound to be reduced contains a halogen substituent in the phenyl ring or acyl. group s it is preferable to use an oxidizable aluminum alkoxide such as aluminum isopropyb ate as the reductant since the metallic catalysts used in the catalytic method of hydrogenation and some of the metals (such as sodium, potassium and the like) used in the nascent hydrogen method of reduction tend to remove the halogen atom during the reaction.

The conversion of the a-acylamino-p-hydroxw,

inorganic base, an alkaline salt of an organicacid, ancrganic tertiary base, an aromatic sulfonic acid or sulfuric acid. The acylation can, in general, be carried out at a temperature varying from about 10 to 140 C. but the preferred temperature for'the reaction is between about 60 and 120 C. An inert organic solvent such as benzene, petroleum ether, toluene and the like can be used for the reaction ifdesired although in most cases it is more expedient to omit the use of a solvent and to merely use an excess of the acylating agent. Some of the catalysts which can be used to bring about the reaction in a shorter period of time are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium acetate, pyridine, quinoline, triethylamine, N-ethyl morpholine, N-methyl piperidine, N,-N-dimethyl aniline, p-toluene sulfonic acid and sulfuric acid.

The products of the invention are particularly useful as intermediates in the synthesis of organic compounds possessing antibiotic activity. For example, the products produced in Examples 1, 2 or 3 can be converted to (l) --l-p-nitrophenyl- 2 dichloroacetamidopropane 1,3 diol, a compound possessing outstanding and unique anti-' biotic properties, by the methods described inthe copending application of Crooks et al. Serial No. 15,264, filed March 16, 1948, now Patent No. 2,483,884.

The invention is illustrated by the followin v examples.

Example 1 A mixture consisting of 48 g. of w-benzoylaminoacetophenone, 7.2 g. of paraformaldehyde and 0.2 g. of potassium carbonate in 300 cc. of methanol is allowed to stand at room temperature for eighteen minutes. The reaction mixture is added to one liter of ice water and the gummy solid which separates collected and washed with water. The crude a-benzamido-fimydroxypropiophenone,

Hi Y ila...

thus obtained is dissolved in 400 cc. of ethanol. 5 g. 'of Raney nickel is added to the solution and the mixture shaken with gaseous hydrogen under about 50 lbs. per sq. in. pressure for three to four hours at room temperature. The catalyst is removed by filtration and the filtrate heated to boil- (dl) 11-1-phenyl-2-benzamido-propane -1,3- diol.

The formula of this product which melts at 166-7 C. after-recrystallization from ethanol is,

(61 11 Form The filtrate from the separation ofthe (d1)- pseudo form of the product is evaporated to dryness in vacuo and the crude regular or cis struc- 6 tural form of the benzamido diol purified by recrystalllzation from methanol. Its formula is,

(dB-Beg. form Example 2 (a) A mixture consisting oi! 6 g. or u-benzoylaminoacetophenone, 0.2 g. of sodium bicarbonate and 1.5 g. of paraformaldehyde in 50 cc. 01' methanol is warmed at 45 to 50 C. for one-halt hour to obtain a clear solution. The reaction mixture is allowed to stand for one hour and then poured into 300-400 cc. of ice water. The precipitated product is collected, washed with water and purified by recrystallization from ethanol to obtain the pure. a-benzamido-p-hydroxypropiophenone melting at 137-41 C.

(b) A mixture consisting of 6 g. of w-benzoylaminoacetophenone, 0.1 g. of sodium and 1.5 g. of paraformaldehyde in 50 cc. of methanol is allowed to stand at room temperature until the solution becomes clear, about five minutes. The reaction mixture is immediately poured into 300 cc. of ice water and the desired a-benzamidofl-hydroxypropiophenone isolated and purified as describedin (a).

(c) A mixture consisting of 6 g. of w-benzoylaminoacetophenone, 0.2 g. of potassium carbonate and 3 g. of paraformaldehyde in a solvent mixture composed of 30 cc. of methanol and 10 cc. of water is stirred at room temperature for about ten minutes.

(e) 25 g. of a-benzamido-B-hyd roxypropim phenone, prepared by any of the above methods, is dissolved in 300 cc. of methanol and 0.5 g. of palladium oxide hydrogenation catalyst added to the solution. The mixture is shaken with gaseous hydrogen under a pressufe of about 50 lbs. per sq. in. at room temperature until the theoretical amount of hydrogen has been taken up.

The catalyst is removed by filtration and the methanol filtrate concentrated to a volume of about 200 cc. An equal volume of hot water is added to the solution and the (d1) -4/-1-phenyl- 2-benzam'idopropane-L3-diol which separates on cooling is collectedand purified by recrystallization from methanol.

The filtrate from the isolation of the -(dl)- pseudo structural isomer is evaporated to dryness and the crude (d1) -reg.-1-phenyl-2-benzamidopropane-1,3-diol thus obtained purified by recrystallization irom methanol.

It the mixture of the two structural forms of the 1-phenyl-2-benzamidopropane-1.3-diol is desired it can be obtained by evaporation of the methanol reaction mixture after removal of the catalyst.

(j) A mixture consisting of 4 g. of a-benzamido-fl-hydroxypropiophenone and 200 of 5% hydrochloric acid is heated under reflux for about Y The reaction mixture. is

poured into about 300 cc. of ice water and the three to four hours and then evaporated to dryness in vacuo. The residue is taken up in a small amount of water, the solution made alkaline and extracted with ethyl acetate. The ethyl acetate extracts are dried and then the ethyl acetate removed by distillation in vacuo to obtain the desired aamino-fl-hydroxypropiophenone.

(g) 8 g. of a-b6I1Z3ll1idO-fl-1'1YQIOXYPI'OP10- phenone is heated at about 75 C. for one-half hour with-20 cc. of acetic anhydride containing a small amount of concentrated sulfuric acid and then the reaction mixture evaporated to dryness in vacuo. The residual crude a-benzamidofiacetoxypropiophenone is washed with ice water and purified by recrystallization from methanol or ethanol. Its formula is:

- H-CH;0 CH;

trated to a volume of about 80 co. in vacuo, cooled and the catalyst and insoluble organic material removed by filtration. The solid is extracted with boiling alcohol, the extracts cooled and the crude (dl)-1p-1-phenyl-2-benzamido-3-acetoxypropane-l-ol collected. This product which has the formula,

0 0 on i O-CH- H-CHzOC-CH:

(dB-#1 Form can be purified further if desired by recrystallization from alcohol.

The corresponding (d1) -reg. isomer can be obtained from the filtrate of the reaction mixture by evaporation of the methanol. The pure isomer is obtained by recrystallization of the crude material from alcohol-water mixtures.

Example 3 3 g. of Raney nickel hydrogenation catalyst is added to a solution of 15 g. of a-acetamido-fi hydroxypropiophenone in 200 cc. of ethanol and the mixture shaken with gaseous hydrogen under.

a pressure of about 60 lbs. per sq. in. at 30 C. until one mol of hydrogen has been absorbed. The catalyst is removed by filtration, the filtrate containing the desired 1-phenyl-2-acetamidopropane-1,3-d10l heated to boiling and treated with slightly more than an equal volume of hot water. After standing at 0 C. for about twentyfour hours, the crystalline (dD-c-l-phenyl-Z- acetamidopropane-l,3-diol is collected and purlfied by recrystallization from methanol; M. P. 132-3" C. This product has the formula,

an s...

(dB- 1 Form hydroxy-propiophenone and 10 cc. of acetic an-' hydride is warmed to 40 C. and one drop of concentrated sulfuric acid added to the solution. The mixture is allowed to stand for one-half hour and then is evaporated to dryness in vacuo. The residue which consists of a-acetamido-p-acetoxypropiophenone of formula,

is washed with water and purified by recrystallization from ethanol.

a-Acetamido-p-acetoxypropiophenone can also be obtained by heating 5 g. of a-acetamido-p-hydroxypropiophenone at about C. for one-half hour with a mixture consisting of 5 cc. of acetic anhydride and 5 cc. of dry pyridine, evaporating the reaction mixture to dryness, washing the residue with water and purifying the product by recrystallization from alcohol.

10 g. of a-acetamido-,B-hydroxypropiophenone in cc. of 18% hydrochloric acid is heated on a steam bath for forty-five minutes. The reaction mixture is cooled, extracted with ethyl acetate and concentrated to dryness in vacuo. The solid residue which consists of a-amino-fl-hydroxypropiophenone hydrochloride is ground under absolute ethanol, collected and washed with a small amount of absolute ethanol. This product which has the formula,

O -cn-cmon can be purified by recrystallization from hot absolute ethanol; T

A mixture consisting of 20 g. of a-acetamido-pacetoxypropiophenone, 0.5 g. of Raney nickel hydrogenation catalyst and 200 cc. of ethanol is shaken at 25 C. with gaseous hydrogen under a pressure of about 50 lbs. per sq. in. until one mol of hydrogen has been absorbed. The reaction mixture is chilled and the solid removed by filtration. The solid which consists of a mixture of a mixture of (dl) -/-1-phenyl-2-acetamido-3- acetoxypropane-l-ol and the hydrogenation catalyst is extracted with boiling ethanol, the excrystallization from methanol.

tracts cooled and the (d1) --1-phenyl-2-acetamido-3-acetoxypropane-1-ol which separates collected. This compound which has the formula,v

fied by recrystallization from methanol. The formula of this product is:

MEG

l Q1 11-01120 H3 5 g. of a-benzamido-p-hydroxy-2-methylpropiophenone in 150 cc. of 10% hydrobromic acid is heated under reflux for about two hours. The reaction mixture is concentrated to a volume of about 75 co. in vacuo, cooled and the benzoic acid which precipitates removed by filtration. The filtrate is evaporated to dryness in vacuo to obtain the hydrobromide salt of a-amino-p-hydroxy-2-methylpropiophenone. Recrystallization from absolute ethanol yields the pure compound. This product has the formula,

Q -n-omorr 0.5 g. of palladium oxide hydrogenation catalyst isadded to a solution of 20 g. a-benzamido-fl-hydroxy-2-methylpropiophenone in 300 cc. of ethanol and the mixture shaken at room temperature with gaseous hydrogen under a pressure of about lbs. per sq. in. until one mol of hydrogen has been absorbed. The catalyst is removed by filtration, the filtrate containing the desired 1-(2'- methylphenyD-2 benzamidopropane 1,3 diol concentrated to a volume of about 150 cc. and an equal volume of hot water added to the hot solution. After allowing the solution to stand at 0 C. for about twenty-four hours, the crystalline (d1) --l-(2'-methylphenyl) 2 benzamidopropane-1,3-diol is collected and purified by re- Its formula is,

(dl)-x,l/ Form L The filtrate from which the (d1) -pseudo isomer has been separated is evaporated to dryness and the residue taken up and fractionally crystallized (2-methylphenyl) -2 benzamidopropane 1,3- diol of formula,

an-ne form A mixture consisting of 5g. of a-benzamido-flhydroxy-2-methylpropiophenone, 20 cc. of dry pyridine and 20 cc. of benzoyl chloride is allowed to stand at 25 C. for about twenty-four hours, poured into 300 cc. of ice water and the crude abenzamido-p-benzoxy 2 methylpropiophenone collected. This product which has the formula,

, I lFi-CHgO-E-O is purified by washing with water and recrystallization from alcohol.

5 g. of a-benzamido-p-benzoxy-2-methyl propiophenone and 0.5 g. of palladium oxide in cc. of ethanol are shaken at room temperature with gaseous hydrogen under a pressure of about 65 lbs. per sq. in. until one mol of hydrogen is absorbed The reaction mixture is warmed to about 60C.. the catalyst removed by filtration and the filtrate evaporated to dryness in vacuo to obtain the desired, l-(2'-methylphenyl) -2- benzamido-3-benzoxypropane-l-ol of formula.

Example 5 A mixture consisting of 28.5 g. of w-(p-methylbenzoylamino) -3-methoxyacetophenone, 7 g. of

paraformaldehyde and 0.3 g. of calcium hydroxide in 300 cc. of ethanol containing about 25 cc. of water is heated at 35 C. for about twenty to twenty-five minutes. The reaction mixture is poured into one liter of ice water and the a- (p-methylbenzamido) p hydroxy-3-methoxypropiophenone which separates collected. The crude product is washed with water and then purified by recrystallization from ethanol or methanol. Its formula is:

' O NH-lQ-CH:

' 2 Q1- n-cmon evaporated to dryness in vacuo. The crystalline from methanol to obtain the desired (dl)-reg.-1- 15 residue obtained upon evaporation of the aque- Q -oH-cmon This white crystalline salt may be purified by recrystallization from hot absolute ehanol.

15 g. of a-(p-methylbenzamido)-,6-hydroxy-3- methoxypropiophenone is dissolved in 200 cc. of ethanol containing a small amount of water. 4 g. of fine sodium wire is added slowly to the solution keeping the temperature at about 20 C. After all the sodium has dissolved, the reaction mixture is poured into one liter of ice water and acidified with dilute hydrochloric acid in the cold. The solution is exhaustively extracted with ethyl acetate, the combined extracts dried and the ethyl acetate is removed by distillation in vacuo to obtain the desired 1-(3'-methoxyphenyl) 2 (p methylbenzamidol-propane- 1,8-diol of formula.

W OH.

@Jm- H-CEiOH cm If desired, the product can be separated into its two structural isomeric iorms, that is, the (dl) -regular and the (d1) -pseudo forms. by tractional crystallization from methanolor ethanolwater mixtures.

Example 6 O O NHjrE-CHICH C -(BH-CHaOH g. of a-propionamido p hydroxy-3,4-dimetlwlpropiophenone is heated under reflux with 150 cc. of 10% hydrochloric acid for about three hours. The reaction mixture is cooled, extracted with ethyl acetate and the aqueous phase evaporated to dryness in vacuo. The

white crystalline compound thus obtained is the hydrochloride salt oi 4,5-dimethy1-a-amino-.8- hydroxypropiophenone. This salt has the formula.

2 g. of Raney nickel hydrogenation catalyst is added to a solution of g. of a-proprionamido- ,e-hydroxy-3,i-dimethylpropiophenone in 300 cc. of ethanol and the mixture shaken under about 60 lbs. per sq. in. pressure 01' hydrogen gas for several hours. As soon as the hydrogen uptake reaches the theoretical amount the reaction isstopped and the catalyst removed by filtration. The filtrate containing the desired 1-(3',4'-dinethylphenyl) 2 propionamidopropane-L3- diol is evaporated to dryness in vacuo and the crude product separated into its structural isomeric forms by fractional crystallization from methanol or methanol-water mixtures. The higher melting trans or pseudo isomer, that is. (d1 p 1'-(3',-4'-dimethyiphenyl)-2-propionamidopropane-1,3-diol, separates from the crystallization mixture first. Its formula is:

mula.

O OH NH-B-CHzCE;

g5 0B dn-en-omon (dB-Reg. form 30 is recovered from the filtrates.

A mixture consisting of 5 g. of e-propionamido. fl-hydroxy-3,4-dimethylpropiophenone, 10 g. of benzoic anhydride, 0.1 cc. of concentrated sulfuric acid and cc. of benzene is heated at 50 C. for one-halt hour. The benzene is removed by distillationin vacuo and the residue treated with 200- cc. of ice water. The mixture is made alkaline with sodium hydroxide solution and the insoluble product which consists of crude a-Pl'O- 4 pionamido-p-benzoxy-3A-dimethylpropiophenone of formula,

0 NH-PJ-Csflt a. a- HEA collected.

0.5 g. of Raney nickel hydrosenation ca is added to a solution 01 5 g. 01' a-propionamldofl-benzoxy-3,4-dimethylpropiophenone in 150 cc. ethanol and the resulting mixture shaken at 30' C. with gaseous hydrogen under a pressure of about 50 lbs. per sq. in. After one moi of hydrogen has been absorbed, the reaction is stopped. the mixture heated to bo'iling and filtered. Evap oration oi the filtrate yields a mixture or the 69 structural forms oi '1-(3',4-dimethylphenyl) -2- propionamido -.3 benzoxypropane 1, 01. This compound has the formula,

Example 7 A mixture consisting of 25 g. of u-phenylacetamido-i-chloroacetophenone, 0.2 g. of sodium blcarbonate and 5 g. of paraiormaldehyde in 300 Its formulais:

, o o NH-E-Cm-O 0.0%...

g. of e-phenylacetamido-p-hydroxy-4-chloropropiophenone is heated under reflux with 100 cc. of hydrobromic acid for three hours. The reaction mixture is cooled, extracted with ether and the aqueous phase evaporated to dryness in vacuo. The white crystalline residue consists of the desired hydrobromide saltof a-amino- B-hydroxy 4 chloropropiophenone. This compound which can be purified by recrystallization from absolute ethanol has the formula,

A mixture consisting of 15.8 g. of e-phenylacetamldo-fl-hydroxy-d-chloropropiophenone, 10

A mixture consisting of 10 g. of a-phenylacetmido-p-hydroxy-4-chloropropiophenone and cc. of acetic anhydride is heated at 100 C. for about one hour and then the acetic acid and excess acetic anhydride removed by distillation in vacuo. The residue is treated with ice water and purified by recrystallization from ethanol. This product is a phenylacetamido p acetoxy-4- chloropropiophenone which has the formula,

f. i 01 c- HCHzOC--CH:

Example 8 A mixture consisting of g. of p-iodo-u-di- -chloroacetamidoacetophenone, 150 cc. of methanol, 50 cc. of 38% aqueous formaldehyde and 0.5 g. of sodium bicarbonate is heated at 35 C. for one and one-half hours. The reaction mixture is cooled, the solid product collected and washed with water. The crude p-iodo-u-dichloroacetamido-p-hydroxypropiophenone thus obtained is purified by recrystallization from ethanol or methanol. I The formula of this product is,

rO -cn-cmon 5 g. of p-iodo-a-dichloroacetamido-p-hydroxypropiophenone is heated under reflux for two hours with cc. of 18% hydrochloric acid. The reaction mixture is cooled, extracted exhaustively with ethyl acetate and the aqueous phase evaporated to dryness in vacuo. The product thus obtained is the hydrochloride salt of p-iodo-camino-p-hydroxypropiophenone. This salt can be purified by recrystallization from asolute ethanol. Its formula is,

0 NHa-HCI A mixture consisting of '1 g. of D-iOdO-a-dlchloroacetamido-p-hydroxypropiophenone, 6 g. of succinic anhydride and 2 drops of concentrated sulfuric .acid is heated at 60 C. for about one hour. cc. of cold water is added to the reaction mixture and the insoluble product collected. The insoluble product is suspended in 100 cc. of cold water and the solution made alkaline to pH 10 by the addition of 10 N sodium hydroxide solution. The solution is extracted with ethyl acetate, the aqueous phase decolorized with charcoal and the clarified solution acidified with dilute hydrochloric acid. The insoluble product which consists of p-iodo-a-dichloroacetamide p (B'- carboxypropionyloxy) -propiophenone is collected, washed with water and purified by recrystallization from ethanol. The formula of this white crystalline product is,

o l o IO n-cmo cmcmcoon 18 of p-iodo-a-dichloroacetamido-B-hydroxypropiophenone is added to 10 g. of aluminum isopropylate in 250 cc. of dry isopropanol and the mixture refluxed for six hours. During the heating period a stream of nitrogen is passed through the solution and a small amount of the reaction mixture is continuously distilled off. The isopropanol is removed by distillation in vacuo. the residue treated with 250 cc. of water and the mixture heated to boiling. The aluminum hydroxide is removed by filtration and the filtrate evaporated to dryness in vacuo. The residue is washed with several small portions of ethyl acetate and the crystalline solid containing (dl) i' -1-p-iodophenyl-2-dichloroacetamido propanel,3-diol which fails to dissolve collected and recrystallized from water to obtain the desired (dl) I' isomer. This product which has the formula,

. (dl) 41 Form can be purified by recrystallization from ethylene dichloride.

Emample 9 11 g. of w-fluoroacetamidoacetophenone is mixed with 50 cc. of methanol and 1'7 cc. of 38% aqueous formaldehyde. 0.4 g. of sodium bicarbonate is added and the mixture stirred at 35 C. for about one hour during which time the solid product separates. The mixture is cooled, stirred for about one-half hour and the solid product l5 collected. The product thus obtained is a-fluoroacetamido-fi-hydroxypropiophenone of formula,

' iana...

The product is washed with water and purified, if desired, by recrystallization from alcohol.

7.5 g. of a-fluoroacetamido-fi-hydroxypropiophenone is mixed with 4.5 g. of aluminum isopropylate and 75 cc. of dry isopropanol. The mixture is heated under reflux for five hours during which time the acetone formed is distilled ofi and a stream of nitrogen is passed through the solution. The isopropanol is removed by distillation in vacuo and the residue treated with about 200 cc. of water. The mixture is warmed to insure complete precipitation of the aluminum hydroxide, the aluminum hydroxide removed by filtration and the filtrate evaporated to dryness in vacuo. The-residue is washed with several portions of hot ethyl acetate and the material which falls to dissolve collected. The product thus obtained is composed principally of (dl),--1- phenyl-2-fiuoroacetamidopropane-1,3-diol. This product has the formula,

mula,

o NH-a-CHJ l 0 Q H-OHmpJ-CHQ Example 10 A mixture consisting of 15 g. of 3-Chl01'O-w- (e-chloropropionamido)-acetophenone, 6 g. of paraformaldehyde and 0.2 g. of sodium carbonate in 200 cc. of 70% aqueous methanol is stirred at room temperature for about one hour. The reaction mixture is poured into 500 cc. of ice water and the precipitated product collected. The product is washed with water and purified by recrystallization from methanol or ethanol to obtain the desired 3-chloro-a-(a-chloropropionamido) -p-hydroxypropiophenone of formula,

Q-CH-CH:

8 g. of 3-Chl01'O-a- (a' chloropropionamido-phydroxy-propriophenone is added to 6 g. of aluminum isopropylate in 250 cc. of dry isopropanol. The mixture is heated at 50 C. for about twentyiour hours durin which time a stream of nitrogen is passed through the solution. The isopr0- panel is removed by distillation in vacuo and the residue treated with about 200 cc. of water. The

mixture is warmed to insure complete precipitation of the aluminum hydroxide, the aluminum hydroxide removed by filtration and the filtrate evaporated to dryness in vacuo. The residue'ia washed with several portions of hot ethyl acetate and the material which fails to dissolve collected. Recrystallization from water yields the desired (d1) 0-1-(3-ch1orophenyl) -2 a chloroproplonamidopropane-1,3-diol of formula,

(d1) 9 Form 7 g. of 3-chloro-u-(a'-chloropropionamido) -phydroxy-propiophenone is mixed with 8 g. of dry pyridine. and the mixture cooled to 0 C. 5 g. o! chloroacetyl chloride is added dropwise with stirring, keeping the temperature at about 0 C. After the addition has been completed the mixture is stirred for one-half hour and then treated with .150 cc. of ice water. The insoluble product is collected, washed well with water and purified by recrystallization from ethanol or methanol. The white crystalline compound thus obtained is 3- ChlOl'O-a-(a' -chloropropionamido) p chloroacetoxypropiophenone. This compound has the formula. v

. o, l 0 p rucmoJi-cmm 1 Example 11 uam...

A mixture consisting of 15 g. of a-methoxyacetamido-fl-hydroxypropiophenone, 2 g. of Raney nickel hydrogenation catalyst and 250 cc. of ethanol is shaken under 60 lbs./sq. in. pressure of hydrogen gas for several hours. As soon as the hydrogen uptake reaches the theoretical amount the reaction is stopped and the catalyst removed by filtration. The filtrate containing the desired 1-phenyl-2-methoxyacetamidopropane is evaporated to dryness in vacuo and the crude product separated into its structural isomeric forms by fractional crystallization from methanol or methanol-water mixtures. The first isomer to separate from the solution is the (dl) -11 form 7 which ha the formula,

16 an-w Form 7 g. of a-methoxyacetamido-p-hydroxypropiophenone is added to 7 g. of dry pyridine and the mixture cooled to C. 4 g. of .methoxyacetyl chloride is added dropwise with stirring, keeping the temperature at about 0 C. After the addition has been completed the mixture is stirred for a A mixture consisting of 2.86 g. of p-bromo-acetamido-B-hydroxypropiophenone, cc. of acetic anhydride and 1 drop of concentrated sulfuric acid is heated with occasional stirring at 80 C.

' for twenty minutes. The clear yellow solution is 'cooled and 3 cc. of ethyl acetate added to the short time and then poured into about 150 cc of ice water. The insoluble product is collected,

washed well with water and purified byrecrystallization from methanol. The white crystalline compound thus obtained is a-methoxyacetamidop-methoxyacetoxypropiophenone having the formula,

bra-t-omoon,

Qttn-cmot-onzocm Reduction of a-methoxyacetamido-fi-methoxyacetoxypropiophenone with hydrogen using a Raney nickel catalyst results in the production of a mixture of the structural form of 1-phenyl-2- methoxyacetamido -3-methoxyacetoxypropane-1- 01 of formula,

O I i NH- CHzOCH Example 12 2 g. of sodium bicarbonate and 26 cc. of 38% aqueous formaldehyde are added to a, solution consisting of 51.2 g. of p,-bromo-w-acetamidoacetophenone and 150 cc. of 95% ethanol. The mixture is stirred at 40-41" C..for one and a half hours, cooled to 5 C. and stirred for an additional hour. The white crystalline p-bromo-a-acetamido ,B hydroxypropiophenone is collected, Washed With'water and dried at 60 'C.; M. P. 146-8" 0. This compound has the formula,

. H O NH-C-CH:

A mixture consisting of 57.5 g. of p-bromo-a-- acetamido-B hydroxypropiophenone, 86 g. of aluminum isopropylate and 500 cc. of anhydrous isopropanol is heated under reflux for about six hours. During this time a small amount of the reaction mixture is distilled off and tested from time to time for acetone. A solution consisting of 45 cc. of water and 100 cc. of isopropanol is added to the reaction mixture along with 50 g. of aluminum silicate filter aid. The reaction miX ture' is heated for fifteen minutes and filtered while hot. The residue is washed well with isopropanol and the washings together with the filtrate treated with a small amount of water. Upon cooling the crystalline (d1) -x//-1-p-bromophenyl-2-acetamido-propane-1,3-diol separates. The product is collected by filtration and purified, if desired, by recrystallization from water; M. P. 1'768 C. The formula of this product is,,

(d1) 0 Form pasty reaction mixture. The mixture is warmed to effect solution and. then allowed to cool. The crystalline p bromo a acetamido ,3 acetoxypropiophenone which separates is collected, washed with ethyl acetate and purified by recrystallization from ethyl acetate; M. P. 128-30 C. The formula of this compound is,

' o l 0 Br- -t n-cmot i-cm Example 13 i A mixture consisting of 100-g. of p-chloro-wv acetamido-acetophenone, 165 cc. of methanol, 5

g. of sodium bicarbonate and 43 cc. of 38% aqueous formaldehyde is heated at 43-45 C. for about one and a half hours. The solution is cooled and allowed to stand overnight. The crystalline pchloro-a-acetamido e-hydroxypropiophenone is about fifteen minutes.

collected, washed with water and dried at 60 0.;

M. P. 125 6- C. The formula of this product is,

cnOc -tH-cmori A mixture consisting of 2.4 g. of p-chloro-aacetamido-5-hydroxypropiophenone and 5 cc. of acetic anhydride-coritaining a few drops of concentrated sulfuric acid is heated at 70 C. for The reaction mixture is I cooled, poured into about ten volumes of water and tested for acetone.

and the p-chloro-a-acetamido-fl-acetoxypropiophenone which separates in crystalline formcollected. Recrystallization from dilute acetic acid yields the pure product which melts at -125 C. This compound has the formula,

A mixture consisting of 60 g. of p-chloro-aacetamido- 3-hydroxypropiophenone, 108 g. of aluminum isopropylate and 640 cc. of dry isopropanol is heated under reflux for about six hours.

.Duringthis time a small amount of the reaction mOc H-tJH-cmoH Example 14 A mixture consisting of '7 g. of w-m-chlorobenzamidoacetophenone, 0.2 g. of sodium bicarbonate and 1.5 g. of paraformaldehyde in 50 cc. of methanol is heated at 42 C. for one hour. The reaction mixture is allowed to stand for an hour and is then poured into about 400 cc. of ice Water. The precipitated product is collected, washed with water and purified by recrystallization from ethanol to obtain the pure a-m-chlorobenzamidoc-hydroxypropiophenone of formula,

Oi-lm-omon d hmi Example 15 65 g. of p-iodo-w-acetamidoacetophenone is added to 400 cc. of methanol and 2 g. of sodium bicarbonate. 85 cc. of 38% aqueous formaldehyde is added and the mixture heated at 40 C. for one hour. The reactionmixture is cooled, allowed to stand for about an hour and the precipitated p-iodo -a.- acetamido-,B-hydroxypropiophenone collected and washed with water. This product which has the formula,

IGtLoH-cmorr can be purified, if desired, by recrystallization from ethyl acetate; M. P. 158 -9 0'. 1

150 g. of p-iodo-a-acetamido-p-hydroxypropiophenone in 1500 cc. of dry isopropanol is heated O OH NH--CHa (d1) -1,l/ Form 5 g. of p-iodo-a-acetamido-fl-hydroxypropiophenone is heated on a steam bath for one hour with 100 cc. of 18% hydrochloric acid. The solution is concentrated to dryness in vacuo after extraction with ethyl acetate. The solid residue which consists of p-iodo-a-amino-fl-hydroxypropiophenone hydrochloride is washed with a small amount of absolute ethanol and purified by recrystallization from hot absolute ethanol. The formula of this compound is,

NHz-HCl IGc-oH-omoH Example 16 24.6 g. of 2,4-dichloro-w-acetamidoacetophenone is dissolved in 150 cc. of methanol. 0.5 g. of sodium bicarbonate and 10 cc. of.38% aqueous formaldehyde are added to the solution and the mixture warmed until solution is complete. The reaction mixture is cooled, stirred for about an hour and the crystalline 2,4-dichloro-a-acetamido B hydroxypropiophenone collected, washed "with water and dried at 60 C. This white crystalline compound which has the formula,

can be purified, if desired, by recrystallization from ethanol.

A mixture consisting of 3 g. of 2,4-di0h10r0-aacetamido- 8-hydroxypropi0phenone, 6 cc. of acetic anhydride and 2 drops of concentrated sulfuric acid is heated with occasional stirring at C. for about twenty minutes. The clear solution is cooled and ethyl acetate added to the reaction mixture. The mixture is warmed to complete solution and then allowed to cool. The white crystalline 2,4-dichloro -aacetamido 49- acetoxypropiophenone which separates is collected, washed with ethyl acetate and purified by recrystallization from this solvent. The formula of this compound is,

O NH-Hl-CH:

A mixture consisting of 20. g. of 2,4-dichloro-dacetamido- 3-hydroxypropiophenone, 28 g. of aluminum isopropylate and 200 cc. of anhydrous isopropanol is heated under reflux for about six hours. During this time a small amount of the reaction mixture is distilled ofi and tested for acetone. The solution is also blanketed with nitrogen during the refluxing period. The reaction mixture i treated with 25 cc. of water and a small amount of isopropanol, heated to boiling and then filtered. The filtrate is diluted with a small amount of water and cooled. The crystalline (d1) -l/ -1 (2 ,4 -dichlorophenyl) .-2 -acetamidopropane-1,3-diol which separates is collected, washed with water and purified, if desired,

mQcH-cE-omon 1 7 (d1) 19 Form Ex mple 17 0.7 g. of sodium bicarbonate and 10 cc. of 38% aqueous formaldehyde are added to a solution consisting of 22 g. of 2-methyl-4-methoxy-w-acetamidoacetophenone in a mixture consisting of 50 cc. of methanol and 100 cc. of water. The reaction mixture is allowed to warm spontaneously and a small amount of heat from a steam bath applied, if necessary, to effect solution. The reaction mixture is cooled, stirred for about two hours at room temperature and the white crystalline 2-methyl-4-methoxy--acetamido-p-hydroxypropiophenone collected. The product is washed with water and purified, if desired, by recrystallization from benzene. This compound has the formula,

20 g. of 2-methyl-4-methoxy-a-acetamido-phydroxypropiophenone is dissolved in 250 cc. of ethanol and placed in a small hydrogenation bottle. 2 g. of palladium on charcoal catalyst (5%) is added and the mixture hydrogenated at 50 lbs/sq. in. pressure. When the theoretical amount of hydrogen has been absorbed, the catalyst is removed from the solution by filtration and the filtrate evaporated to dryness in vacuo. The residue which consists of a mixture of the isomeric forms of 1-(2'-methyl-4'-methoxyphenyl)-2- acetamidopropane-l,3-diol i treated with about 500 cc. of hot ethyl; acetate and sufficient 95% ethanol to effect solution. The solution is cooled and the crystalline (d1) -reg.-1-(2'-methyl-4'- methoxyphenyl) -2 acetamidopropane 1,3 diol a short time, if necessary, on the steam bath to insure solution. The reaction mixture is cooled, stirred for an additional hour and the white crystalline 2,4-dimethoxy-c-acetamido-p-hydroxypropiophenonecollected, washed with water and dried. If desired, this product can be purified by recrystallization from benzene. The formula of this compou o cHaoQ- -gn-omon I CE] W A mixture consisting of 3 g. of 2,4-dimethoxya-acetamido-p-hydroxypropiophenone and 6 cc. of acetic anhydride is treated with 2 drops of concentrated sulfuric acid. The resulting mixture is heated with occasional stirring at 75 C. for about twenty .minutes. The clear solution is cooled, treated with a small amount of ethyl acetate and then warmed to effect solution. The solution is cooled and the crystalline 2,4-dimethoxy-o-acetamido-p-acetoxypropiophenone' which separates collected, washed with ethyl acetate and purified by recrystallization from ethanol or benzene. The formula of this compound is,

0 NH-A-CH:

O 0 CHaOQE- HCHzO -CHa A mixture consisting of 20 g. of 24-111- methoxy a acetamido B hydroxypropiophewhich separates collected and purified by recrys- I tallization from hot ethanol. The formula of this product is,

. 0 on xn-l s-on,

(dl)-Reg. form The filtrate from the separation of the (d1) -reg. isomer is evaporated to dryness in vacuo and the residue which consists principally of the (d1) -z//- 1-(2-methyl-4'-methoxyphenyl) 2 acetamidopropane-l,3-diol purified by fractional crystallization from ethanol.

Ecdm ze 18 none, 28 g. of aluminum isopropylate and 200 cc. of anhydrous isopropanol is heated under reflux for about six hours. During this time the reaction mixture is blanketed with nitrogen and a small amount of the liquid distilled off and tested from time to time for acetone. The reaction mixture is treated with about 50 cc. of water, heated to boiling and filtered. The filtrate is chilled and the crystalline (d1)--1- (2,4 dimethoxyphenyl)-2-acetamidopropane- 1,3-diol which separates collected. Further quantities of the product can be obtained by concentration of the filtrate. The crude product is purified by recrystallization from water. Its formula is,

i Example 19 100 cc. of water. The reaction mixture is allowed to warm spontaneously and heated, if necessary, in order to effect solution. Theclear solution is cooled, stirred for about an hour and the crystalline 2-chloro-4-methyl a. acetamido-B-hydroxypropiophenone which separates collected, washed with water and dried. This product which can be purified by recrystallization from ethanol has the formula,

O O NH-PJ-CH:

A mixture consisting of g. of 2-chloro-4- methyl-u-acetamido fi-hydroxypropiophenone, 20 cc. of dry pyridine and 20 cc. of benzoyl chloride is allowed to stand at 25 C. for about twenty-four hours. The reaction mixture is poured into about 300 cc. of ice water and the crude 2-ch1oro-4-methyl a acetamido-B-benzoxypropiophenone collected and purified by recrystallization from ethanol. The formula of this product is,

A mixture consisting of 20 g. of 2chloro-4- methyl a acetamido p hydroxypropiophenone, 30 g. of aluminum isopropylate and 200 cc. of anhydrous isopropanol is heated under reflux for about six hours. During this time the reaction mixture is blanketed with nitrogen and a small amount of the liquid continuously distilled ofi. At the end of the refluxing period 50 cc. of Water is added and the reaction mixture boiled for about fifteen minutes. The reaction mixture is filtered while hot and the filtrate cooled. The crystalline (dl) -\p-l(2-chloro-4- methylphenyl) 2 acetamidopropane-1,3 diol which separates is collected and purified by recrystallization from water or ethanol. The formula of this product is,

(dl) Form E sample 20 t 19 g. of 4-methyl-o-acetamidoacetophenone is dissolved in 50 cc. of methanol and 100 cc. of water added to the solution. cc. of 38% aqueous formaldehyde solution and 9 cc. of 4 N sodium carbonate solution are added and the resulting mixture allowed to warm spontaneously. AS soon as the solution becomes clear the reac- Y 24 tion mixture is cooled, allowed to stand for about one hour and the desired white crystalline 4- methyl-a-acetamido fl hydroxypropiophenone collected. Recrystallization from benzene yields the pure product melting at 22 C. This compound has the formula,

O NH-PJ-CH;

22.1 g. of a-methyl-a-acetamido-B-hydroxypropiqphenone is dissolved in 250 cc. of ethanol and 2 g. of palladium on charcoal hydrogenation catalyst is added. The mixture is placed in a small hydrogenation bottle, a small amount of water added and the mixture hydrogenated at 50 lbs. pressure of hydrogen at room temperature until 8 lbs. of hydrogen have been absorbed. The catalyst is removed by filtration and the filtrate evaporated to dryness in vacuo. The residue is treated with 500 cc. of hot ethyl acetate and sufficient ethanol to effect solution. Upon cooling the (dl) -reg.-1-(4-methylphenyl) -2-acetamid0- propane-1,3-diol separates from the solution. This product which can be purified by recrystallization from ethanol has the formula,

orn-QcH-dH-omoH (dl)-Reg. form and melts at 175-77 C. when pure.

The filtrate from the separation of the (dl) -reg. isomer is evaporated to dryness in vacuo and treated with cc. of hot ethanol. Upon cooling to room temperature an additional 2 g. of the (dl) -reg. isomer separates. The (dl) -reg. isomer is removed by filtration and the filtrate cooled in a refrigerator overnight. The crystalline (dl) 1 (4 methylphenyl) 2 acetamidopropane- 1,3-diol which has separated from the cold solution is collected; M.P. 142-6 C.

A mixture consisting of 3 g. of p-methyl-aacetamido pl hydroxypropiophenone, 6 cc. of acetic anhydride and 3 drops of concentrated sulfuric acid is heated on a steam bath at 80 C. for twenty minutes. The clear solution is cooled, diluted with about 10 cc. of ethyl acetate and then warmed to eflect solution. The solution is allowed to cool and the crystalline 4methyl-a-acetomidofl-acetoxypropiophenone which separates collected, washed with ethyl acetate and purified by recrystallization from ethyl acetate. The formula of this compound is,

H NH-C-CH;

i? l i CHOC- n-orrz'oc i-cm Example 21 'tillation and tested for acetone.

25 not can be purified by recrystallization from methanol. Its formula is,

. cmoQ -on-cmon A mixture consisting of 3 g. of 3,4-dimethoxy-adichloroacetamido-p-hydroxypropiophenone, 6 cc. of acetic anhydride and a few drops of concentrated sulfuric acid is heated at 75 C. for a few minutes. The clear reaction mixture is cooled, diluted with ethyl acetate and then heated to effect solution. The warm mixture is cooled and the crystalline 3,4-dimethoxy-a-dichloroacetamido-fl-acetoxypropiophenone collected and purifled, if desired, by recrystallization from methanol. The formula of this product is,

A mixture consisting of g. of 3,4-dimethoxyc-dichloroacetamido-B-hydroxypropiophenone, g. of aluminum isopropylate and 250 cc. of dry isopropanol is heated under reflux for about six hours. During this time a small amount of the reaction mixture is continuously removed by dis- The w acyl aminoacetophenone derivatives used as starting materials in the practice of the invention can be prepared in several different ways. One of the most satisfactory methods is that described by Lister and Robinson [J Chem. Soc., 101, 1297 (1912)] for the preparation of u-benzoylaminoacetophenone. This involves the conversion of acetophenone to phenylglyoxal, aldoxime followed by reduction with stannous chloride and benzoylation with benzoyl chloride. Another method of preparing these starting materiab involves the reduction of an w-nitroacetophenone followed by acylation of the w-aminoace tophenone obtained on reduction.

What I claim is:

l. A compound of the formula,

where R is a member of the class consisting of hydrogen and carboxylic acid acyl radicals, R1 and R2 are members of the class consisting of hydrogen, halogen, lower alkyl and lower alkoxy radicals and R, is a member of the class consisting of hydrogen and carboxylic acid acyl radicals.

2. A compound of the formula,

Oaxaca...

said Acyl being a carboxylic acid acyl radical.

3. A compound of the formula,

0 NH-Acyl said Acyl being a carboxylic acid acyl radical.

4. A compound of the formula,

5. A compound of the formula,

0 NH&

6. A compound of the formula,

7. A compound of the formula,

O -cn-cmon 8. Process which comprises condensing a compound of formula,

DtLCHmH-R" R2 R, NH-R @o-dn-cmon R:

where R" is a carboxylic acid acyl radical and R1 and R2 are members of the class consisting of hydrogen, halogen, lower alkyl and lower alkoxy radicals.

LOREN M. LONG.

No references cited. 

1. A COMPOUND OF THE FORMULA, 